Rab18 Collaborates with Rab7 to Modulate Lysosomal and Autophagy Activities in the Nervous System: an Overlapping Mechanism for Warburg Micro Syndrome and Charcot-Marie-Tooth Neuropathy Type 2B.
Nian, Fang-Shin; Li, Lei-Li; Cheng, Chih-Yaet al.
2019 • In Molecular Neurobiology, 56 (9), p. 6095 - 6105
2019 Nian-Rab18 Collaborates with Rab7 to Modulate Lysosomal and Autophagy Activities in the Nervous System an Overlapping Mechanism for Warburg Micro Syndrome and CMT Neuropathy Type 2B.pdf
[en] Mutations in RAB18, a member of small G protein, cause Warburg micro syndrome (WARBM), whose clinical features include vision impairment, postnatal microcephaly, and lower limb spasticity. Previously, our Rab18-/- mice exhibited hind limb weakness and spasticity as well as signs of axonal degeneration in the spinal cord and lumbar spinal nerves. However, the cellular and molecular function of RAB18 and its roles in the pathogenesis of WARBM are still not fully understood. Using immunofluorescence staining and expression of Rab18 and organelle markers, we find that Rab18 associates with lysosomes and actively traffics along neurites in cultured neurons. Interestingly, Rab18-/- neurons exhibit impaired lysosomal transport. Using autophagosome marker LC3-II, we show that Rab18 dysfunction leads to aberrant autophagy activities in neurons. Electron microscopy further reveals accumulation of lipofuscin-like granules in the dorsal root ganglion of Rab18-/- mice. Surprisingly, Rab18 colocalizes, cofractionates, and coprecipitates with the lysosomal regulator Rab7, mutations of which cause Charcot-Marie-Tooth (CMT) neuropathy type 2B. Moreover, Rab7 is upregulated in Rab18-deficient neurons, suggesting a compensatory effect. Together, our results suggest that the functions of RAB18 and RAB7 in lysosomal and autophagic activities may constitute an overlapping mechanism underlying WARBM and CMT pathogenesis in the nervous system.
Disciplines :
Genetics & genetic processes
Author, co-author :
Nian, Fang-Shin ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan ; Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
Li, Lei-Li; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
Cheng, Chih-Ya; Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan
Wu, Pei-Chun; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan ; Brain Research Center, National Yang-Ming University, Taipei, Taiwan
Lin, You-Tai; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
Tang, Cheng-Yung; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
Ren, Bo-Shiun; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
Tai, Chin-Yin; Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan
Fann, Ming-Ji; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan ; Brain Research Center, National Yang-Ming University, Taipei, Taiwan
Kao, Lung-Sen; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan ; Brain Research Center, National Yang-Ming University, Taipei, Taiwan
Hong, Chen-Jee; Brain Research Center, National Yang-Ming University, Taipei, Taiwan ; Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan ; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
Tsai, Jin-Wu ; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan. tsaijw@ym.edu.tw ; Brain Research Center, National Yang-Ming University, Taipei, Taiwan. tsaijw@ym.edu.tw ; Biopotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei, Taiwan. tsaijw@ym.edu.tw
Language :
English
Title :
Rab18 Collaborates with Rab7 to Modulate Lysosomal and Autophagy Activities in the Nervous System: an Overlapping Mechanism for Warburg Micro Syndrome and Charcot-Marie-Tooth Neuropathy Type 2B.
We appreciate Dr. Mu-Ming Poo (University of California, Berkeley), Dr. Chih-Chiang Chan (National Taiwan University), and Ms. Elise Shen (University of Texas, Austin) for helpful comments and suggestions. The authors also wish to thank the Instrumentation Resource Center, National Yang-Ming University, and the National RNAi Core Facility at Academia Sinica, Taiwan for their technical support.Funding This work was supported by the grants of Yen Tjing Ling Medical Foundation (CI-103-4), the Ministry of Science and Technology (NSC 101-2320-B-010-077-MY2, 102-2314-B-075-079, 103-2628-B-010-002-MY3, 104-2633-H-010-001, 104-2745-B-075-001, 105-2633-B-009-003, 106-2321-B-075-001, 106-2628-B-010-002-MY3, and 107-2321-B-075-001), Taipei Veterans General Hospital-University System of Taiwan (VGHUST106-G7-5-2), National Health Research Institutes (NHRI-EX103-10314NC), and Academia Sinica, Taiwan (AS-104-TP-B09 and 2396-105-0100) to JWT; and Taiwan National Science Council (NSC 102-2314-B-075-005-MY3), Taipei Veterans General Hospital (V103E9-004 and V102C-173), and the Ministry of Education Taiwan, Aim for the Top University Plan to CJH. This work is also supported by the Development and Construction Program of NYMU School of Medicine (107F-M01-0502) and the Brain Research Center, NYMU through the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), Taiwan.
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